Opportunities and Challenges for

Development of Monoclonal Antibodies for

Use in Rabies Post-Exposure Prophylaxis
FDA Public Workshop
Sarah Connelly, MD
Senior Medical Officer, Division of Antiviral Products
July 17, 2017
 Today’s Public Workshop
Objective: Discuss the challenges and identify additional
scientific work needed to advance development of
monoclonal antibodies (mAb) targeting rabies virus for use
in a post-exposure prophylaxis (PEP) regimen, to be used in
conjunction with licensed rabies vaccine.
• Public workshop to facilitate sharing of the available data
and complexities in the field of rabies PEP
– Note: Not an advisory committee, decisional meeting, or
regulatory meeting on any specific product or products
• Forum for discussion and for identifying research gaps
relevant to regulatory and public health issues

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 Rabies Background
• Fatal encephalitis of mammals resulting from rabies virus
infection
• No established current treatment; survival is rare
– ~55,000 deaths/year worldwide (95% Asia, Africa, Latin America)
• Prevention
– Animal vaccination
– Pre-exposure prophylaxis (PrEP)
• Rabies vaccine
– Post-exposure prophylaxis (PEP)*
• Rabies vaccine plus immunoglobulin (*if prior PrEP, only vaccine)
• ~11,000-36,000 persons/year receive PEP in the US
• 15+ million persons/year receive PEP worldwide

Christian KA, et al. Epidemiology of rabies post-exposure prophylaxis--United States of America, 2006-2008.. Vaccine. 2009 Nov 27;27(51):7156-61
http://www.who.int/rabies/human/situation/en/ 3
http://virology-online.com/viruses/Rhabdoviruses.htm
 Global Risk of Rabies

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http://www.who.int/rabies/Global_distribution_risk_humans_contracting_rabies_2013.png?ua=1
Rabies Virus Vectors

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 Rabies Pathogenesis After Animal
Exposure

Jackson, A.C., 2007. Pathogenesis. In: Jackson, A.C., Wunner, W.H. (Eds.),
Rabies, second ed. Elsevier Academic Press, London, pp. 341–381 6
 Dynamics of Rabies Virus
Pathogenesis

Adapted from CDC. Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies: 7
Recommendations of the Advisory Committee on Immunization Practices. MMWR 2010;59(No. RR-2).
 Role of PEP After Animal Exposure

Role of PEP

Jackson, A.C., 2007. Pathogenesis. In: Jackson, A.C., Wunner, W.H. (Eds.),
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Rabies, second ed. Elsevier Academic Press, London, pp. 341–381
 RIG as a Component of Rabies PEP
• ACIP by Animal Type
– Skunks, raccoons, fox, bats regarded as rabid unless (-) testing
– Dogs, cats, ferrets can be watched for 10 days if not suspected rabid
– Livestock, rodents low risk
• WHO by Exposure
– Category II: Nibbling of uncovered skin, minor scratches or abrasions (without
bleeding). PEP recommendation does not include RIG.
– Category III: Single/multiple transdermal bites or scratches, licks on broken skin;
contamination of mucous membranes with saliva (licks); contacts with bats
• Regimen (if have not received prior PrEP):
– Begin as soon as possible, though no time limitation for initiation
ACIP WHO Category III Exposures
Extensive wound cleansing Day 0 Day 0
RIG^ HRIG Day 0* HRIG or ERIG Day 0*
Rabies vaccine IM Day 0, 3, 7, 14 IM Day 0, 3, 7, 14, 28 or Day 0, 7, 21
ID Day 0, 3, 7, 28
(Thai Red Cross schedule)
^As much as anatomically feasible should be infiltrated in area around/in wound: any remaining dose IM
*Do not administer RIG after Day 7 of rabies vaccine (in cases where delayed RIG)
CDC. Human rabies prevention---United States, 2008: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2008;57(No. RR-3). 9
WHO Expert Consultation on Rabies. Second report. WHO Technical Report Series 982 (2013) http://apps.who.int/iris/bitstream/10665/85346/1/9789240690943_eng.pdf (accessed 7/11/2017)
 Rabies Vaccine-Mediated
Immune Response

Adapted from CDC. Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies: 10
Recommendations of the Advisory Committee on Immunization Practices. MMWR 2010;59(No. RR-2).
 Contribution of Passive
Immunization to PEP Regimen

Adapted from CDC. Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies: 11
Recommendations of the Advisory Committee on Immunization Practices. MMWR 2010;59(No. RR-2).
 Rabies Immunoglobulin
US approved Human RIG Products
HyperRAB S/D
The usefulness of prophylactic rabies antibody in preventing rabies in humans when administered
immediately after exposure was dramatically demonstrated in a group of persons bitten by a rabid wolf in
Iran. Similarly, beneficial results were later reported from the U.S.S.R. Studies coordinated by WHO
(World Health Organization) helped determine the optimal conditions under which antirabies serum of
equine origin and rabies vaccine can be used in man. These studies showed that serum can interfere to a
variable extent with the active immunity induced by the vaccine, but could be minimized by booster doses
of vaccine after the end of the usual dosage series.

Imogam
Controlled human trials of Rabies Immune Globulin (Human) have not been performed; however,
extensive field experience from many areas of the world indicates that post-exposure prophylaxis
combining local wound treatment, local infiltration of rabies immune globulin (RIG), and vaccination is
uniformly effective when appropriately administered.

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6183eb49-fd6e-4ec2-b41f-8a8dcbd9d4f0
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bf845cf8-7c01-46c0-97cb-e73a121ff3a7 12
 Perspective on Use of Current PEP
Regimens
• Available approved/licensed rabies vaccine and
RIG products are considered highly effective at
preventing a highly lethal disease
• Global challenges of utilization of, and access to,
the recommended complete PEP regimen
components
– Supply, cost, and storage considerations

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 Perspectives on Rabies mAb
Development
“More research, development and assessment are needed of suitable
immunoglobulins or alternatives, such as human monoclonal
antibodies, in rabies prophylaxis to ensure wider access to passive
immunization at a reduced cost.”
- WHO Expert Consultation on Rabies. Second Report

Industry

WHO Academics

Rabies mAb
Development

WHO Expert Consultation on Rabies. Second report. WHO Technical Report Series 982 (2013) 14
http://apps.who.int/iris/bitstream/10665/85346/1/9789240690943_eng.pdf (accessed 7/11/2017)
Issues in Assessing Activity of Rabies mAb as
a Component of the PEP Regimen

Nonclinical Data Serologic Assays Clinical Trials

• Breadth of • Passive • Non-rabies-

coverage vs protection exposed
diverse rabies during first few population
virus strains days of PEP
• Selection of mAb • Effects on • Suspected rabies-
dosing regimens rabies vaccine exposed
for initial clinical response population
evaluations

http://www.criver.com/products-services/basic-research/find-a-model/lvg-golden-syrian-hamster?loc=US
https://www.cdc.gov/rabies/specific_groups/doctors/serology.html
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 Clinical Trials with Rabies mAb
Non-Rabies-Exposed Population
• Study of different components (and combined regimens) of
established and proposed PEP in non-rabies-exposed healthy
volunteers
• Initial exploration of tolerability and adverse event profile
• mAb dose exploration
– Can higher doses be identified as excessively interfering with
active response to vaccine?
– Can lower doses be identified as unlikely to provide adequate
protection during the earliest time period before protective
vaccine response begins to be established?
• What serologic assay parameters (level and timing) are most
predictive of protection after rabies-exposure?

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 Clinical Trials with Rabies mAb
Suspected Rabies-Exposed Population (1)
• What is the best achievable understanding from clinical
trials in the suspected rabies-exposed population that a
novel rabies mAb product provides protection from
developing a lethal disease?
– Important not only because of statutory regulatory needs for
evidence supporting efficacy, but also important for public
health and clinical decision-making.
• Hypothetical trial designs and considerations of trial
endpoints will be presented to invite discussion on
studying and interpreting the contribution of rabies mAb
to PEP regimen
– Superiority, non-inferiority, other possible trial designs
– Mortality, other measurements (e.g., serology)
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 Clinical Trials with Rabies mAb
Suspected Rabies-Exposed Population (2)
Challenges in assessing passive-antibody contribution to PEP
regimen
• Multiple factors affect risk of rabies after suspected exposure, such as:
– Was the biting animal rabid?
– Was the animal shedding rabies virus?
– How close is the bite to the nervous system?
– Could the bite site be promptly identified and thoroughly cleaned?
– Is appropriate rabies vaccination series initiated and completed?
– Is passive antibody delivered appropriately?

Objective of effective PEP is to decrease risk of developing rabies, but the

effect of any one factor on this risk (including rabies mAb) may be hard to
measure in any feasible clinical trial – and possibly even harder to
accurately deduce from less-controlled use and experience.

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 Ethical Considerations
• What are important ethical considerations
when designing clinical trials of a rabies mAb-
based PEP product as an alternative to available
hyperimmune globulins?
• What are the ethical considerations for
enrollment of children in rabies mAb clinical
trials?

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 Questions to Consider
• What can be learned from:
– animal data?
– serologic data?
– WHO, Industry, and Academic experiences?
– clinical trials?
• What is the nature and strength of data supporting direct
links between any specific in vitro, animal, or serologic
assessments and contribution of a specific component and
dose of PEP to human clinical outcomes?
• What are the research gaps in understanding the contribution
of rabies mAb to the PEP regimen?
• What are potential uses and limitations of possible clinical
trial designs?
• What are ethical considerations in rabies mAb trial designs?
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“It is better to debate a question without settling
it than to settle a question without debating it.”
– Joseph Joubert, French essayist

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